Receptor downregulation through degradation is an important way for a cell to regulate its response to a given signal. For many receptors, this occurs through endocytosis in clathrin-coated pits followed by degradation in lysosomes. It has recently been recognized, however, that elements of the ubiquitin-proteasome pathway, the cellular apparatus for degrading cytoplasmic proteins, are also important in downregulating a variety of receptors. The serine/threonine kinase receptors are a newly described class of cell surface receptors which comprise the TGF-beta receptor superfamily. The TGF-betas are powerful growth factors with many functions, including modulation of adhesion, the immune response, and proliferation. Elements of the TGF-beta signaling pathway, including its receptors, are abnormal in a variety of cancers, most notably colon cancer. Although cellular responses to the TGF-betas are likely to be tightly regulated, little is known about the control of receptor number at the cell surface. The general goal of this proposal is to understand the mechanism of degradation and ligand-mediated downregulation of the type I and type II TGF-beta signaling receptors. Preliminary experiments show that degradation of cell surface type II receptor (TbetaRII) occurs in the proteasome. The experiments proposed here are therefore designed to answer the following specific questions: 1. What is the signal for TbetaRII degradation? Specifically, is the receptor ubiquitinated, and, if yes, what is the relationship between ubiquitination, receptor internalization, and proteasomal degradation? 2. What is the signal for TGF-beta-induced TbetaRII instability? 3. Is the type I receptor also degraded in proteasomes? What are the signals for its degradaton and ligand-mediated downregulation? By describing the degradation of a class of receptors not previously studied, these investigations will add significantly to our general knowledge about the cellular degradation machinery and its interaction with the plasma membrane. The results will also contribute to our understanding of TGF-beta receptors and the TGF-beta response by examining the way in which cells regulate the numbers and ratios of cell surface type I and type II TGF-beta receptors and thereby potentially regulate the quality and magnitude of the response to TGF-beta.